Aberrant cell state plasticity mediated by developmental reprogramming precedes cancer initiation [CUT&RUN]

Cell state (phenotypic) plasticity is a carefully regulated feature of adult epithelial cells that enables adaptive responses to injury, inflammation, and other forms of stress.Aberrant expansion of the normally restricted capability for cell state plasticity to escape terminal differentiation is a critical aspect of neoplasia. The nongenetic factors and specific programs that mediate aberrant cell state plasticity and impaired differentiationrequire deeper characterization to understand this elusive aspect ofcancer pathogenesis. Using genetically engineered andcarcinogen-induced murine models of intestinal neoplasia, wedemonstrate that impaired differentiation is a conserved eventpreceding cancer development. Single cell RNA-sequencing (scRNA-seq)of neoplastic intestinal lesions from both mouse models and a patientwith familial adenomatous polyposis revealed that cancer initiates byadopting an aberrant transcriptional state characterized bynonoverlapping expression of a regenerative pathway, marked by Ly6a(Sca-1), and a fetal intestinal program, positive for Tacstd2 (Trop2).Genetic inactivation of Sox9 prevented adenoma formation in ApcKOmice, obstructed emergence of aberrant regenerative and fetalintestinal programs, and restored multi-lineage differentiation byscRNA-seq. Expanded chromatin accessibility at regeneration and fetalgenes upon Apc inactivation was reduced by concomitant Sox9suppression. These studies indicate that aberrant cell stateplasticity mediated by unabated regenerative activity anddevelopmental reprogramming precedes cancer development. Overall design: Cleavage Under Targets & Release Using Nuclease (CUT&RUN) for SOX9 in Adenoma and Normal organoids derived from a patient with Familial Adenomatous Polyposis syndrome.